Embryos, Cloning, Stem Cells, and the Promise of Reprogramming

Neural rosettes, derived from human embryonic stem cells, assemble into spheres in culture. (Credit: Gist Croft / Ali Brivanlou / Rockefeller University)

Excerpt from The Art and Politics of Science, by Nobel Laureate Harold Varmus (W. W. Norton, 2010). Reprinted with permission from the author.

Chapter 13: Embryos, Cloning, Stem Cells, and the Promise of Reprogramming

Over the past decade, stem cell research has become the most visible and contentious manifestation of the promise of biological science, akin to the Human Genome Project in the 1990s or recombinant DNA research and biotechnology in the 1970s and 1980s. The term “stem cells”—shorthand for the controversial type, human embryonic stem cells—is now widely recognized, and it represents a defining issue for candidates in national and local politics.

To a biologist, “stem cells” has a precise meaning, encompassing more than the human embryonic type that attracts political attention. All of the many specialized cells in animal and humans beings have developed through an orderly process in which cells divide and differentiate. At the beginnings of these developmental pathways are immature cells with the capacity to produce two types of daughter cells when they divide: one daughter cell is indistinguishable from its parents (and has the same capacities), while the other has taken a step toward specialization. These immature cells, which both renew themselves and produce differentiated offspring, are called stem cells. Many stem cells reside in adult tissue and have restricted abilities to differentiate, becoming cells only in a particular organ, such as the skin, the liver, the brain, or the blood system. But stem cells with much greater potential are abundant much earlier in animal development, in the first stages, the early embryo. These early embryonic stem cells can serve as precursors to all of the cells that form the tissues and organs of a mature animal; because of this “plural” potential, they are called pluripotent.

Embryonic stem cells have achieved prominence in part because of the still unsubstantiated hopes that therapies that use them can ameliorate a variety of human ailments. They have attracted controversy mainly because the cells are obtained from human embryos, linking stem cell research to historical battles over abortion and over the legal and moral status of the human embryo and fetus.

The current debates about stem cells and the policies governing their use were influenced by three pivotal events that occurred during my tenure as director of the NIH in the 1990s: an NIH panel’s prophetic report in 1994 about the prospects for research on the early human embryo; the birth of the lamb named Dolly, the first animal cloned from an adult cell, in 1997; and the isolation and growth of pluripotent stem cells from very early human embryos in 1998. To understand the nature and history of the debates, it is helpful to consider how these three topics —embryo research, reproductive cloning, and embryonic stem cells—are interwoven, both biologically and politically. It will also be important to describe newer methods, less controversial than those involving the use of embryos, that can also produce pluripotent cells. Together, these developments have changed our concepts of biological systems and driven political discussions of science to new levels of complexity.

Each of the three events in the 1990s had a defining characteristic. The 1994 report on human embryo research, inspired by scientific opportunities arising largely from then recent work with mouse embryos, recommended that many (but not all) of those opportunities be pursued by the NIH with human cells and embryos. The report also anticipated important advances in mammalian biology that might allow embryo-related research to be applied beneficially in clinical settings. Although written in response to a new and potentially permissive political environment, changes in the political climate soon led to prohibitions that continue to limit much of the research recommended in the report. The birth of Dolly in 1997 was a remarkable scientific accomplishment, which fundamentally altered the way that biologists view the control of genetic information in animal cells. It revealed a greater than expected capacity to “reprogram” cells—to reset the genetic program that guides development. But Dolly’s birth also unleashed fears about human reproductive cloning, and these have restricted the pursuit of a promising method for reprogramming cells for therapeutic purposes. Finally, the advent of research on human embryonic stem cells, following the growth of the first lines of such cells in 1998, moved the ethical debates about the use of human embryos from speculation to pragmatic immediacy, with clear implications for the pace at which such research would proceed in this country.

Thinking about Research with Human Embryos

Any account of recent developments in embryo research, cloning, and stem cells must begin at least a few decades before animal clones and human embryonic stem cells were announced, with brief descriptions of two underlying accomplishments: the successful development in the United Kingdom of in vitro fertilization (IVF) procedures in the late 1970s and the flowering of genetic engineering with experimental mice in the 1980s.

The birth of Louise Brown, the first child conceived by IVF, in England in 1978, fundamentally changed the perspectives of society toward the early stages of human development.[1] The idea of manipulating life, by allowing fertilization of an egg by a sperm cell to occur in a test tube, and then implanting a tiny embryo into a receptive uterus days later, met with expected resistance. But the initial resistance has by now been overwhelmed by the success of IVF procedures to treat reproductive failures, allowing many thousands of infertile couples to enjoy the satisfactions of bearing and raising children.

In the years immediately following the initial successes of IVF, the U.S. government established a requirement that any proposed research on human fertilization, embryos, or the later fetal stage of development must be reviewed by an ethics advisory board before federal funds could be used to support it. From 1980 until 1993, in the administrations of Ronald Reagan and George H. W. Bush, no board was ever assembled and no federal dollars were ever spent on such research. Consequently, IVF work in this country was largely confined to clinical use, often in the private sector; improvements in IVF methods came largely from research done abroad. Furthermore, no federally supported research was performed to explore the use of cells or tissues from aborted fetuses or from unused early embryos to treat human diseases, such as Parkinson’s disease, that were caused by loss of normal cells.

In 1993, Bill Clinton’s arrival in Washington reactivated the possibility of supporting research on the developing forms of human beings—embryos and fetuses. Among the new president’s first actions was to sign a new NIH reauthorization bill that removed prior constraints on the use of federal funds for research with human fetal tissue and embryos.[2] Soon thereafter, NIH began to fund fetal tissue research—for example, clinical trials of fetal brain cell treatments for Parkinson’s disease—under guidelines that already existed for the ethical acquisition and use of fetal tissues.

But no administration had considered the prospects of research on human materials from a much earlier stage of development, the preimplantation embryo. This stage normally begins with the fertilization of an egg by a single sperm cell, forming a one-cell embryo, also called the zygote, that divides several times during the next ten to fourteen days, after which the embryo normally implants in the way of the uterus. At that point, the embryo begins to form the three basic tissue layers that are precursors to many types of cells present in mature organs, even though no recognizable nervous system or other organs are yet discernible.

Preimplantation human embryos had been produced commonly for many years by IVF, the union of a donate egg and sperm in a test tube, with the intention of producing offspring for otherwise infertile couples. A few days after IVF, embryos that appear viable are placed in a woman’s birth canal in hopes that one or more will implant in the uterine wall and develop into a normal baby. However, not all embryos produced by in vitro fertilization are actually used in efforts to produce new offspring, either because the embryos do not appear normal or, more commonly, because the IVF clinic has generated more embryos that were needed to achieve a couple’s reproductive goals.

Because research on the IVF process or the resulting early embryos had never been conducted with federal funds in the United States, either before or after the birth of Louise Brown, there were no guidelines or regulations for such studies. This meant that the federal funding of human embryo research in any of its aspects—in vitro fertilization, formation of the zygote (the fertilized egg), the early cells divisions, and first steps in differentiation of these tiny clumps of human cells—would have to be deferred until the various types of embryo research could be more carefully evaluated and guidelines proposed.

There were good reasons to examine the prospects. During the preceding two or three decades, biologists had made enormous progress by studying the early development of embryos of mice, the most widely studied mammal. It is relatively easy to obtain fertilized eggs from laboratory mice and then observe the subsequent cell divisions until the embryos comprise fifty to one hundred cells or more and are ready for implantation into the female reproductive tract. At this stage, disaggregated cells from the mouse embryos can grow and divide indefinitely in petri dishes when fed appropriately. These cells are also able to develop into all kinds of organs or tissues. For instance, if they are injected into an intact embryo, which is then allowed to mature into a newborn mouse, descendants of the stem cells can contribute to any part of the mature animal. Thus they meet the definition of a pluripotent stem cell: they divide to yield daughter cells that are indistinguishable from the starting cells (“self-renewal”), and they differentiate into a wide variety of types (“pluripotency”).

Over the past couple of decades, work with early mouse embryos—and with stem cells derived from them—has been dramatically enhanced by some powerful new methods that allow genetic modification of the mouse germ line and rigorous study of mammalian gene functions. DNA mapping and sequencing—features of the Mouse Genome Project—have defined the genetic composition and organization of mouse chromosomes and identified genes that are involved in the formation and function of specific tissues. Genes that govern normal development and produce disease are now routinely studied in mice by altering the genetic makeup of the early embryo. This can be done in either of two ways. First, genes can be added to the mouse germ line, putting them directly into fertilized eggs, and the genes will then be transmitted to mouse progeny.[3] Before this maneuver, the genes can be mutated to mimic genetic alterations observed in human diseases or engineered to be expressed as an investigator wishes. In the second approach, any gene in a cultured embryonic stem cell can be specifically targeted to make mutations that explore normal functions of the gene or recapitulate mutations found in human diseases.[4] Again, by appropriate manipulations, these mutations can enter the germ line of mature mice. These two methods have been extraordinarily important for studying normal functions and many diseases in a mammalian species, but they are currently, and appropriately, forbidden in human beings.

By 1993, work with mouse embryos had stimulated many provocative and testable ideas about how early cells differentiate to form mature tissues and about how diseases arise. These ideas are pertinent to analogous human events, in part because of the great similarities observed between mice and human beings when their genomes, biochemical properties, and cell functions are compared. By the early 1990s, it was also widely appreciated that many human embryos were stored in freezers and destined for destruction at IVF clinics in the United States and elsewhere, because they had been kept in a frozen state too long for efficient implantation in a uterus or because the sperm and egg donors had either already achieved parenthood or had abandoned attempts to reproduce for other reasons. Thus, many kinds of work on human embryos would be feasible without creating additional embryos for research purposes.

But what work ought to be pursued? Late in 1993, after legal constraints on federal funding of human embryo and fetal tissue research had been eased, my NIH colleagues and I assembled a group to think about this question. The Human Embryo Research Panel was asked to survey the experimental possibilities in the realm of human embryo research and recommend the ones that deserved to be pursued with federal funds, on the basis of scientific merit, possible medical applications, and ethical implications.

We were fortunate to attract a wide range of eminent people, from several fields of medical science, jurisprudence, and ethics, to serve on the panel, including, as chair, Dr. Steven Muller, a former president of Johns Hopkins University. The group met repeatedly over the next year, in both open and closed sessions; commissioned reports on several ethical, medical, and scientific aspects of embryo research; and debated each decision with vigor and intelligence. As requested, the panel offered thoughtful judgments about the kinds of studies that should be supported with federal funds, which should not be supported, and which should be postponed for consideration until more information was available or further discussion had occurred.

Looking back on the panel’s lengthy report today,[5] with our much deeper knowledge about embryos, cloning, and stem cells, I find its pre-science truly astonishing. The panel anticipated by a few years several major developments, including the derivation of stem cells from human embryos and the use of cloning methods in embryo research. And it made prophetic observations about how those developments might be used for medical benefit. In particular, the panel foresaw in 1994 the prospect of growing human embryonic cells from early embryos, even though no stem cells from any primate embryo had yet been grown in the laboratory. From earlier work with mice, members of the panel knew that embryonic stem cells were likely to have the potential to develop into many specific tissue types; if so, they could be used to repair damaged tissues or to treat chronic degenerative diseases of the brain or spinal cord, endocrine organs (such as the pancreatic islets), muscles, joints, or other tissues.

But the panel also recognized the biological difficulties such therapies might pose. For example, cells from preexisting embryos would likely be different genetically from the patients who received embryonic stem cell therapies. If so, the immune system of the patient would reject the transplanted cells as foreign. For this reason, the panel argued that it might sometimes be acceptable to create embryos that more adequately represent the full range of human genetic diversity. This would be done using IVF, with sperm and eggs donated by adults from varied ethnic origins. Stem cells derived from these embryos would increase the likelihood of good matches between the cells used in therapy and the recipients (patients). But the generation of immunological diversity in this fashion would also cross an ethical line that a couple of panel members were unwilling to cross: the creation of human embryos for purposes other than reproduction—in this case, medical research and treatment.

Excerpted from The Art and Politics of Science by Nobel Laureate Harold Varmus. Copyright © Harold Varmus, 2009. All rights reserved.

[1] R. G. Edwards, B. D. Bavister, and P. C. Steptoe, “Early stages of fertilization in vitro of human oocytes matured in vitro,” Nature 221 (15 Feb. 1969): 632-35; P. C. Steptoe and R. G. Edwards, “Birth after the reimplantation of a human embryo,” Lancet 312 (12 Aug. 1978): 366.
[2] http://history.nih.gov/research/downloads/PL103-43.pdf.
[3] R. D. Palmiter and R. L. Brinster, “Transgenic mice,” Cell 41 (1985): 343-45.
[4] M. R. Capecchi, “Gene targeting in mice: Functional analysis of the mammalian genome for the twenty-first century,” Nature Reviews Genetics 6 (June 2005): 507-12.
[5] National Institutes of Health, Report of the Human Embryo Research Panel (27 Sept. 1994).

Harold Varmus is an American Nobel Prize-winning scientist and the 14th and current Director of the National Cancer Institute, a post he was appointed to by President Barack Obama. He was a co-recipient (along with J. Michael Bishop) of the 1989 Nobel Prize in Medicine for discovery of the cellular origin of retroviral oncogenes. He previously served as President and Chief Executive Officer of Memorial Sloan-Kettering Cancer Center (MSKCC), Director of the National Institutes of Health (NIH) and co-chair of the President’s Council of Advisors on Science and Technology.

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